This proposal, entitled the Consortium for Alzheimer's Sequence Analysis (CASA) describes plans to analyze whole exome and whole genome sequence data generated from subjects with Alzheimer's disease (AD) and elderly normal controls. These data will be generated by the National Human Genome Institute Large-Scale Sequence Program. The goal of the planned analyses is to identify genes that have alleles that protect against or increase susceptibility to AD. This is a multiple PI proposal, a collaboration between five senior AD genetics investigators (Farrer, Haines, Mayeux, Pericak-Vance, Schellenberg). CASA has 4 cores and 3 projects. Core A is the Administrative core that will coordinate all aspects of CASA. Core B is the Analysis Statistics and Innovation core that will design and assist analysis by other cores/projects and devise novel methods of statistical analysis. Core C is that Data Management and Information Transfer Core that will implement analyses designed by Core B and the projects. Core C will provide high-performance computing for CASA. These three cores are mandated by FOA PAR-12-183. Core D is the In Silico Functional Genomics Core that will annotate AD-associated variants and perform pathway and interaction analyses. Project 1 will evaluate variants detected in the sequence data for association with AD to identify protective and susceptibility alleles. Project 2 will evaluate sequence data from multiplex AD families to identify variants associated with AD risk and protection, and evaluate variant co-segregation with AD. Project 3 will focus on structural variants (insertion-deletions, copy number variants, and chromosomal rearrangements). The project will use existing methods and develop and implement novel approaches for detecting structural variants. The projects and cores are highly interdependent. For example, structural variants identified by Project 3 will be integrated with single nucleotide AD-associated variants identified by Projects 1 and 2. Likewise variants identified by Project 1 will be tested in the family-based data sets. Core B will assist all projects in designing analyses and Core C will implement Project analyses. Core D will annotate and help interpret results from all projects.